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Title: Prospective CCR5 Small Molecule Antagonist Compound Design Using a Combined Mutagenesis/Modeling Approach
Authors: Metz, Markus ×
Bourque, Elyse
Labrecque, Jean
Danthi, Sanjay J
Langille, Jonathan
Harwig, Curtis
Yang, Wen
Darkes, Marilyn C
Lau, Gloria
Santucci, Zefferino
Bridger, Gary J
Schols, Dominique
Fricker, Simon P
Skerlj, Renato T #
Issue Date: Oct-2011
Publisher: American Chemical Society
Series Title: Journal of the American Chemical Society vol:133 issue:41 pages:16477-16485
Abstract: The viral resistance of marketed antiviral drugs including the emergence of new viral resistance of the only marketed CCR5 entry inhibitor, maraviroc, makes it necessary to develop new CCR5 allosteric inhibitors. A mutagenesis/modeling approach was used (a) to remove the potential hERG liability in an otherwise very promising series of compounds and (b) to design a new class of compounds with an unique mutant fingerprint profile depending on residues in the N-terminus and the extracellular loop 2. On the basis of residues, which were identified by mutagenesis as key interaction sites, binding modes of compounds were derived and utilized for compound design in a prospective manner. The compounds were then synthesized, and in vitro evaluation not only showed that they had good antiviral potency but also fulfilled the requirement of low hERG inhibition, a criterion necessary because a potential approved drug would be administered chronically. This work utilized an interdisciplinary approach including medicinal chemistry, molecular biology, and computational chemistry merging the structural requirements for potency with the requirements of an acceptable in vitro profile for allosteric CCR5 inhibitors. The obtained mutant fingerprint profiles of CCR5 inhibitors were used to translate the CCR5 allosteric binding site into a general pharmacophore, which can be used for discovering new inhibitors.
ISSN: 0002-7863
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

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